SUMMARY Managing blood glucose with CGMs, insulin pumps, or integrated artificial pancreas systems has been shown to increase clinical outcomes for people with diabetes. However, not all patients with diabetes adopt these technologies because they are a) painful, b) invasive, and c) expensive. The three FDA- approved tools for real-time monitoring for glucose must all be implanted in the body for 7-14 days, making them neither ideal for people with Type I nor desirable for the hundreds of millions of people with Type II diabetes/pre-diabetes. We envision a painless, wireless, small form-factor and inexpensive daily CGM which gives people with diabetes the freedom to wear the device easily and when they choose. A sufficiently easy, painless and effective device which could monitor glucose as well as other analytes would also increase the likelihood of early diagnosis for diabetes and a host of other conditions. Specifically, we have engineered a CGM which overcomes these key limitations. Our ?strip-on-chip? leverages microneedle technology and magnetic actuation to insert and remove individual needles the size of a human hair. This platform allows us to painlessly and accurately sample interstitial fluid from dermal and epidermal tissue (~1 mm). Since the needles are exceedingly small and only transiently embedded within the skin, microneedle-based sensing is less invasive and causes less foreign body response. Additionally, manufacturing the needles with high reproducibility leads to simpler factory calibration, decreasing the cost of the device to roughly the cost of an existing test strip. Importantly the ?strip-on-chip? can be easily and painlessly applied; removed at any time; and reapplied without changing the sensor module. The goal of this proposal is to determine the operating space and calibration space of our novel sensing and strategy for accessing sample. A successful outcome of this phase I application is two-fold: (1) to determine that our sensor can perform in vitro as well, if not better than, the 3 FDA-approved CGM devices on the market; and (2) to validate that our sensor can support a painless, minimally invasive, calibration-free CGM device. This will provide the data necessary for the FDA IDE and feasibility human trial and the development of a sound manufacturing process that is at the heart of our Phase II proposal.